The goal of this project is multifold. One goal is to study the structure-activity relationships of cocaine and its analogs in terms of its binding to the transporter. The more potent analogs are obviously useful as in vitro and in vivo binding ligands. Also, and this is becoming a bigger part of our work, many of these compounds are quite possibly useful as substitute agonist medications, much like methadone or the nicotine patch, in human psychostimulant abusers. We published two new studies on novel cocaine analogs and their ability to bind to the dopamine transporter. Amide analogs (in the C2 position) are highly potent and highly selective for the dopamine transporter. This is yet another group of compounds that have these properties. Unfortunately, in experiments where we've radiolabeled various potent and selective amide-containing cocaine analogs, we found that while they were excellent in vitro binding ligands for the dopamine transporter, they did not cross the blood-brain barrier and could not be used in vivo, either as binding ligands or as behaviorally active probes. A series of QSAR studies of a variety of cocaine analogs extended our knowledge from the binding data obtained in structure-activity work and elucidated features of the cocaine pharmacophore. These studies also provide interesting predictive information about novel analogs. Thus, additional compounds will be synthesized using the calculations. RTI-121 is a potent and selective dopamine transporter inhibitor. Investigators from our team made the compound in a radiolabeled form and showed, as predicted by the binding data, that it is an excellent in vitro binding compound. It had high affinity, was selective for the transporter, and had a pharmacology completely consistent with binding to the dopamine transporter. This compound can be used not only in vitro, but also in vivo as a PET or SPECT ligand. There appears to be much interest in this substance and we expect that it will become a fairly heavily utilized ligand. We continue to identify novel analogs. Dr. Ivy Carroll, the chemist supervising the synthetic work, continues to be enthusiastic about this project.